Most colorectal cancers (CRCs) arise from adenomatous precursors. Accumulated oncogene and tumor suppressor gene (TSG) defects underlie adenoma development and progression of some lesions to carcinoma. Gene defects with key roles in tumor initiation, progression, and maintenance are termed "drivers". A "passenger" defect might simply have arisen coincident with a driver alteration. Sorting out driver and passenger defects in CRC will likely require in-depth work. Even for well-established TSGs, their role in the cancer process often remains enigmatic. During the prior period, we described novel CDX2P-Cre transgenic mice and their use for somatic inactivation of the Apc TSG in cecum, colon and rectum, leading to new models of colonic adenoma-carcinoma progression. These novel CDX2P-Cre transgenic mice are of great utility for somatic gene targeting of candidate driver genes in CRC. We also generated a conditional knockout of Cdx2 and have found Cdx2 inactivation in colon epithelium yields interesting gene dosage-dependent effects. The overarching goal of this competing renewal application is to define the functional contribution of gene lesions in CRC, emphasizing work where selected TSGs are somatically targeted in mouse colorectal epithelium. The specific aims are: I) Define the contribution of Cdx2 defects in colon tumorigenesis;and II) Define the role of p53 missense mutations in promoting colorectal adenoma- carcinoma progression. The aims are united by commonalities in approach and the goal of testing key concepts in the CRC field, such as how multiple gene defects collaborate in tumor progression. Besides providing a key functional assessment of selected TSGs in CRC, the studies should offer new mechanistic clues about the gene defects. The colon tumor models also represent a new direction, as small intestinal tumor models have dominated work in the field to date. PUBLIC HEALTH RELEVANCE: Statement Besides providing a critical functional test of the contribution of selected gene lesions in colorectal cancer (CRC) development, the proposed studies will allow other advances, such as: I) mechanistic insights into specific gene lesions in CRC;and II) the establishment of relevant models to study environmental and dietary factors in CRC and new strategies for cancer detection, chemoprevention, and therapeutic intervention.